The invention relates to the use of niacin derivatives and niacin in the regulation of leptin modulated pathways. Specifically, niacin and its derivatives, such as nicotinate esters, lauryl nicotinate ester in particular, stimulate production of leptin, with ramifications as discussed infra.
Leptin, a 167 amino acid protein encoded by the ob gene, was identified in the course of research in identifying molecular defects in an obesity prone strain, i.e., the xe2x80x9cob/obxe2x80x9d mouse. It has been found that leptin is produced for the most part in white adipose tissue, with very small amounts being found in brown adipose tissue. Exemplary of the patent literature relating to this molecule are U.S. Pat. Nos. 6,132,724; 6,124,448; 6,124,439; 6,068,976; 6,048,837 and 5,795,909, all of which are incorporated by reference.
The first reports on leptin suggested that it was an adipocyte derived, signaling molecule, which limited food intake and increased energy expenditure, i.e., an xe2x80x9cadiposat.xe2x80x9d The evidence supporting this included observed decreases in body weight, and improved metabolic control in rodents that evidenced genetic or diet induced obesity that were injected with leptin. In the case of ob/ob mice, which have mutations in the ob gene, leading to synthesis of defective leptin molecules that are degraded intracellularly, the effect of leptin is especially pronounced. The ob/ob mice are obese, diabetic and sterile, and exhibit reduced activity, metabolism, and body temperature. In addition, leptin-deficient ob/ob mice suffer from seriously delayed wound healing. Systemic or topically administered leptin has been shown to improve re-epitheliazation of wounds in this model. See Frank, et al., J. Clin. Invest. 106: 501-509 (2000). As such, the ob/ob mouse has been used as a model system for testing drugs for their ability to reverse impaired wound healing.
In addition to the effect on leptin deficient mice, discussed supra, leptin markedly promoted re-epitheliazation in wild type mice. In addition, STAT 3 and peroxisome-proliferator activated receptor (xe2x80x9cPPARxe2x80x9d hereafter), which are the downstream regulators in the leptin pathway, are involved in skin homeostasis. See Komuvres, et al., J Invest. Dermatol 115:361-267 (2000). STAT 3 has been shown to play an essential role in skin remodeling, including hair follicle cycling and wound healing. It is also known that PPARxcex1 activators normalize cell proliferation, including epidermal differentiation, and accelerate the development of the epidermal permeability barrier. See Hanley, et al., J. Clin Inv. 100:705-712 (1997). Recently, it has been demonstrated that PPARxcex1 activators inhibit murine skin tumor promotion. This is consistent with PPARxcex1 having a role in skin physiology. See Thuillier, et al., Mol. Carcinogenesis 29:134-142 (2000).
Further research on leptin has revealed that the molecule alters the transcription of several adipose specific genes involved in lipogenesis, lipolysis, and energy metabolism. It also appears to trigger apoptosis in white adipose tissue. Most of the molecule""s metabolic effects appear to result from specific interactions with receptors located in the central nervous system, and in peripheral tissues. The receptor has been identified and is a Class I cytokine receptor that belongs to a family that includes the IL-2 receptor, interferon receptor and growth hormone receptor. In brief, the leptin receptor transmits leptin signal to the three STAT molecules STAT 3, 5, and 6, referred to collectively as the xe2x80x9cfat-STATS.xe2x80x9d
The accepted view of leptin is that its primary role is to prevent obesity via regulating food intake and thermogenesis via action on hypothalomic centers. Recent evidence suggests, however, that leptin may have an additional role, i.e., it may exhibit antisteatotic activity, in that fatty acid over-accumulation in non-adipose tissue may be prevented by leptin mediated regulation of xcex2-oxidation. Leptin increases enzymes involved in fatty acid oxidation and stimulates a previously unobserved form of lipolysis, where glycerol is released without proportional release of free fatty acids.
Various leptin receptor isoforms are expressed throughout the body suggesting that leptin has additional physiological functions on extra-neural tissue. Studies have been carried out to evaluate tissue responsiveness to leptin, via determining what effects, if any, it has on glucidic and lipidic metabolism, as well as expression of some enzymes. If a direct effect of leptin on a given tissue is observed, it implies rapid induction of signal transduction mechanisms, flowing from hormone/receptor binding. Essentially the mechanism of action can be summarized as follows: leptin activates STAT 3 in adipose tissue, binding of leptin to its receptor leads to receptor oligomerization, and JAK activation, leading in turn to STAT phosphorylation; phosphorylated STATS dimerize and translocate into nuclei, where they activate target genes. In brief:
(i) Leptin activates STAT 3, and increases PPARxcex1 activity;
(ii) PPARxcex1/PPRE induces apo A-I expression in liver cells;
(iii) STAT3/PPARxcex1 is essential for skin homeostasis;
(iv) PPARxcex1 activators inhibit mouse skin tumor promotion.
See, e.g. Bendinelli, et al., Mol. Cell Endocrin 168:11-20 (2000); Unger, et al., Proc. Natl. Acad. Sci USA 96:2327-2332 (1992); Peters, et al., J. Biol. Chem. 272:27307-27312 (1997); Hanley, et al., J. Clin. Invest. 100:705-712 (1997); Sano, et al., EMBOJ 18:4657-4666 (1999); Thuillier, et al., Mol. Carcin 29:134-142 (2000).
In addition to playing a role in energy regulation, leptin also regulates endocrine and immune functions. Leptin levels increase acutely during infection and inflammation, and may represent a protective component of the host response to inflammation. Leptin deficiency increases susceptibility to infectious and inflammatory stimuli and is associated with dysregulation of cytokine production. See Faggioni, et al., FASEB J. 15:2565-2571 (2001).
In addition, it can be hypothesized that the pathway described supra can also lead to skin homeostasis and remodeling, which in turn leads to epidermal barrier development, wound healing, and hair growth, as well as the inhibition of skin tumor promotion caused by increased immune functions. This is summarized in FIG. 1.
Niacin is essential to formation of the coenzymes nicotinamide dinucleotide (NAD), and NAD phosphate (NADP), where the nicotinamide moiety acts as an electron acceptor or hydrogen donor in many biological redox reactions. To elaborate, NAD functions as an electron carrier for intracellular respiration, and as a coenzyme in the oxidation of fuel molecules. NADP acts as a hydrogen donor in reductive biosynthesis, including fatty acid and steroid synthesis. As is the case with NAD, it also acts as a coenzyme.
NAD is the substrate for three classes of enzymes that transfer ADP-ribose units to proteins involved in DNA repair, cell differentiation, and cellular calcium mobilization. Nicotinic acid, in contrast to nicotinamide, when given in doses of 1.5-4 g/day improves blood cholesterol profiles.
Acipimox, a commercially available, nicotinic acid analog and hypolipodemic agent, was shown to increase plasma leptin levels in transgenic mice. See, e.g., Worm, et al., Eur. J. Endocrin 143:389-395 (2000).
It has been shown that nicotinic acid derivatives have efficacy in, inter alia, skin cell protection, DNA repair, etc. See, e.g., U.S. Pat. No. 6,337,065, filed Dec. 1, 1999 to Jacobson, et al., incorporated by reference in its entirety. This application describes various nicotinic acid derivatives, including a dodecyl, or lauryl nicotinic acid ester. It has now been found that such nicotinic acid esters, such as lauryl nicotinic acid ester, stimulate leptin production to an extent not seen with niacin. As the nicotinic acid esters can be formulated as e.g., materials suitable for topical application, a new approach to leptin stimulation and production is provided.